Cerebral ischemia remains a major problem for patients requiring anesthesia and surgery. Our work is devoted to understanding the effects of anesthesia on ischemic brain damage.We have shown that rats anesthetized with halothane have reduced injury when compared to rats undergoing ischemia while awake. This protection is not attributable to effects on brain temperature, plasma glucose, perfusion pressure, or cerebral metabolic rate. We postulate that the protective effect may, in part, be attributable to reduction of adrenergic responses to ischemia. We will first extend the halothane protection observation to a more commonly used anesthetic agent, isoflurane. Effects of both of these drugs on the frequency of spontaneous depolarizations and tissue PO2 in the focal ischemic penumbra will be defined. We will then compare effects of different anesthetic states, which produce known differences in circulating catecholamine concentrations, on histologic outcome from near- complete (isoelectric EEC) and incomplete (attenuated EEC) global ischemia. We expect differences in outcome to occur only during incomplete ischemia. We speculate that anesthetic effects on brain extracellular adrenergic neurotransmitter concentrations will be of importance only when ischemia induced changes in brain catecholamine concentrations are small (i.e., incomplete ischemia). During more severe (near-complete) ischemia, anesthetic effects are expected to be inconsequential given massive release of endogenous catecholamine stores. To verify this we will correct for anesthetic differences by administration of exogenous catecholamines or by sympathetic ganglionic blockade. Corollary studies will use microdialysis to associate plasma and brain extracellular catecholamine concentrations to histologic outcome as a function of severity of the ischemic insult. To specifically examine effects of endogenous brain catecholamine concentrations on anesthetic differences in outcome, lesions of the locus coeruleus and substantia nigra will be used to inhibit ischemia induced release of norepinephrine and dopamine. Corollary in vitro studies using primary neuronal cultures will examine adrenergic neurotransmitters as neurop rotectants against glutamatergic excitotoxicity and how these adrenergic neurotransmitters modulate neuroprotection provided by volatile anesthetic agents.